Purpose
This trial was conducted to confirm the non-inferiority of remimazolam versus propofol in the induction and maintenance of general anesthesia in surgical patients.
Methods
Surgical patients (
...n
= 375) were randomized to remimazolam started at 6 or 12 mg/kg/h by continuous intravenous (IV) infusion until the loss of consciousness (LoC), followed by 1 mg/kg/h to be adjusted as appropriate until the end of surgery or IV propofol administered as a slow bolus of 2.0–2.5 mg/kg until LoC followed by 4–10 mg/kg/h until the end of surgery. Efficacy was measured via the combined primary endpoint of no intraoperative awakening/recall, no need for rescue sedatives, and no body movements. Adverse events and adverse drug reactions (ADRs) were monitored for safety.
Results
Efficacy rates were 100% in all treatment groups, and the non-inferiority of remimazolam was demonstrated 95% confidence interval (− 0.0487; 0.0250). The time to LoC was longer in the remimazolam 6 (
p
< 0.0001) and 12 mg/kg/h (
p
= 0.0149) groups versus propofol. The time to extubation was longer in both remimazolam groups versus the propofol group (
p
≤ 0.0001). The incidence of ADRs was similar in the remimazolam groups (39.3% and 42.7%, respectively) compared with the propofol group (61.3%). Decreased blood pressure occurred in 20.0% and 24.0% of patients treated with 6 and 12 mg/kg/h remimazolam, respectively, compared with 49.3% of patients receiving propofol. Injection site pain was reported in 18.7% of propofol patients but not in those receiving remimazolam.
Conclusions
This trial demonstrated that remimazolam was well tolerated and non-inferior to propofol with regard to efficacy as a sedative hypnotics for general anesthesia.
Clinical trial registration
This trial is registered with the Japan Pharmaceutical Information Center - Clinical Trials Information (JapicCTI). JapicCTI number: 121973
Purpose
Remimazolam, an ultra-short-acting benzodiazepine sedative is equally effective as propofol in induction and maintenance of general anesthesia with improved hemodynamic stability in American ...Society of Anesthesiologists (ASA) Class I and II patients. This trial investigated remimazolam’s efficacy and safety in vulnerable patients (ASA Class III) undergoing elective general surgery.
Methods
A multicenter, randomized, double-blind, parallel-group trial in 67 adult surgical patients undergoing general anesthesia with two remimazolam induction doses (6 mg kg
−1
h
−1
—group A and 12 mg kg
−1
h
−1
—group B) has been conducted in 6 trials sites in Japan. Remimazolam was infused up to 2 mg kg
−1
h
−1
for maintenance of anesthesia in both groups.
Results
The functional anesthetic capability of the investigated drug was 100% in both arms. The mean time to loss of consciousness (LoC) was significantly shorter in group B (81.7 s) compared to group A (97.2 s),
p
= 0.0139. The mean bispectral index (BIS) value during maintenance of anesthesia ranged from 46.0 to 68.0 and from 44.7 to 67.5 in group A and B, respectively. There was no statistically significant difference between the remimazolam arms concerning the incidence of blood pressure (BP) decrease (67.7% in group B vs. 54.8% in group A), recovery profile or the incidence or severity of adverse events (AEs) or adverse drug reactions (ADRs).
Conclusion
Both induction regimens (6 and 12 mg kg
−1
h
−1
) were equally efficacious and safe in surgical patients ASA Class III. A significantly shorter time to LoC was observed with the higher remimazolam dosage.
Clinical trial registration
This trial is registered with the Japan Pharmaceutical Information Center—Clinical Trials Information (JapicCTI). JapicCTI number: 121977.
A cyclic tetramer of pyrene, 4cyclo‐2,7‐pyrenylene (4CPY), was synthesized from pyrene in six steps and 18 % overall yield by the platinum‐mediated assembly of pyrene units and subsequent reductive ...elimination of platinum. The structures of the two key intermediates were unambiguously determined by X‐ray crystallographic analysis. DFT calculations showed that the topology of the frontier orbitals in 4CPY was essentially the same as those in 8cycloparaphenylene (8CPP), and that all the pyrene units were fully conjugated. The electrochemical analyses proved the electronic properties of 4CPY to be similar to those of 8CPP. The results are in sharp contrast to those obtained for the corresponding linear oligomers of pyrene in which each pyrene unit was electronically isolated. The results clearly show a novel effect of the cyclic structure on cyclic π‐conjugated molecules.
Changing the landscape: A cyclic tetramer of pyrene, 4cyclo‐2,7‐pyrenylene (4CPY), was synthesized by the platinum‐mediated cyclotetramerization and subsequent dehydrogenation. DFT calculations and electrochemical analyses showed that the electronic structure of 4CPY was completely altered from that of pyrene and linear oligopyrenes. The results clearly show there is modulation of the topology of molecular orbitals upon formation of a cyclic structure.
10Cycloparaphenylene (10CPP) was selectively synthesized in four steps in 13% overall yield from commercially available 4,4′-diiodobiphenyl by using mono-I–Sn exchange, Sn–Pt transmetalation, I–Pd ...exchange, and subsequent oxidative coupling reactions. The single-crystal X-ray structure of 10CPP is described.
A quantitative approach for the development of halogen‐bonding‐driven anion‐binding catalysts was studied using 4‐substituted perfluorinated iodobenzene. 19F NMR titrations were used to determine the ...binding constants K for chloride, and their catalytic activities were evaluated in the allylation reaction of a N‐activated pyridine. We discovered that the log K and product yields were linearly correlated, and that they were dependent on the Hammett substituent parameter, σmeta (r2=0.99). This linear correlation provided a quantitative predictive model for both the binding constant and the reaction yield. Concomitantly, this efficiently permitted the development of a highly active anion‐binding catalyst, namely 4‐CNC6F4I (K=489±5 M−1). Additionally, the catalytic activity of 4‐CNC6F4I was established in the allylation and crotylation of N‐activated isoquinolines (7 examples). Overall, this approach highlights the value of quantitative analysis by exploring experimentally informed correlations in the development of halogen bond donor catalysts.
A quantitative approach for the design of halogen bond (XB)‐driven anion‐binding catalysts has been developed by revealing the correlation of the Hammett substituent parameter (σmeta) with the product yield. The 4‐CNC6F4I XB donor catalyst was identified to be a more active catalyst than C6F5I. This work provides an important direction for the design of new XB donor catalysts, and leads to the development of a valuable reaction.
The mechanism of Brønsted acid‐initiated formal 1,3‐rearrangement was rationalized using density functional theory (DFT) calculations. The computed mechanism comprises I) fragmentation: (a) ...imino‐nitrogen protonation, (b) proton transfer to olefin, (c) 1,2‐shift, and (d) C−C bond cleavage, and II) product formation: (e) methylene addition, (f) azonia‐3,3‐sigmatropic rearrangement, and (g) methylene elimination. The ene‐aldimine fragmentation to the 2‐azaallenium cation was found to be a highly reactive intermediate and the real catalyst species. The stereoselectivity for asymmetric formal 1,3‐rearrangement of optically pure ene‐aldimine is in good agreement with chair transition state of azonia‐3,3‐sigmatropic rearrangement step and is supported by DFT calculation. Our computational study provides important mechanistic insights for ene‐aldimine rearrangements and guides the design of chiral catalysts for rearrangement process.
The mechanism of Brønsted acid‐initiated 1,3‐rearrangement of ene‐aldimine is studied using density functional theory (DFT) calculations. DFT calculations suggest 2‐azaallenium‐mediated chain reaction where H+ works as an initiator. High stereoselectivity in asymmetric 1,3‐rearrangement reaction is rationalized by a chair transition state in the 2‐azonia‐3,3‐sigmatropic rearrangement step of the reaction intermediate.
An aromatic saddle was designed from the hypothetical three-dimensional graphene with the negative Gaussian curvature (Schwarzite P192). Two aromatic saddles, tetrabenzo8circulene (TB8C) and its ...octamethyl derivative OM-TB8C, were synthesized by the Scholl reaction of cyclic octaphenylene precursors. The structure of TB8C greatly deviates from planarity, and the deep saddle shape was confirmed by single-crystal X-ray crystallography. There are two conformers with the S 4 symmetry, which are twisted compared to the DFT structure (D 2d ). The theoretical studies propose that the interconversion of TB8C via the planar transition state (125 kcal mol–1) is not possible. However, the pseudorotation leads to a low-energy tub-to-tub inversion via the nonplanar transition state (7.3 kcal mol–1). The ground-state structure of TB8C in solution is quite different from the X-ray structure because of the crystal-packing force and low-energy pseudorotation. OM-TB8C is a good electron donor and works as the p-type semiconductor.
This dose-response study investigated the effects of sialorphin on Met
enkephalin (ME)-induced inhibition of contractions in mouse vas deferens and antinociception in male rats. Differences were ...compared among combinations of three chemical peptidase inhibitors: amastatin, captopril, and phosphoramidon. The ratio of potencies of ME in mouse vas deferens pretreated with both sialorphin (100 µM) and a mixture of the three peptidase inhibitors (1 µM each) was higher than that with the mixture of peptidase inhibitors alone at any dose. Intrathecal administration of sialorphin (100-400 nmol) significantly and dose dependently increased ME (3 nmol)-induced antinociception with the mixture of three peptidase inhibitors (10 nmol each). The degree of antinociception with a combination of any two of the peptidase inhibitors (10 nmol each) in the absence of sialorphin was less than that in the presence of sialorphin (200 nmol). Pretreatment with both sialorphin (200 nmol) and the mixture of three peptidase inhibitors (10 nmol each) produced an approximately 100-fold augmentation in ME (10 nmol)-induced antinociception, but without signs of toxicity such as motor dysfunction in rats. Radioligand receptor binding assay revealed that sialorphin did not affect either binding affinity or maximal binding capacity of d-Ala
,
-MePhe
,Gly-ol
enkephalin. These results indicate that sialorphin potentiates the effects of ME without toxicity by a mechanism other than peptidase inhibition and with no effect on its affinity to
-opioid receptors. SIGNIFICANCE STATEMENT: Sialorphin is regarded as an endogenous peptidase inhibitor that interacts with enkephalin-degrading enzymes. The results of these in vitro and in vivo studies confirm that sialorphin potentiates the effects of Met
enkephalin without toxicity by an action other than peptidase inhibition. This suggests that sialorphin offers the advantage of reducing or negating the side effects of opioid drugs and endogenous opioid peptides.
The postanesthesia care unit (PACU), which is run and coordinated by anesthesiologists, delivers general medical supervision as well as close and constant care to patients who have just undergone a ...surgical procedure under anesthesia. Although PACU management has been considered a standard procedure in many developed countries since the 1940s, Japanese hospitals have tended to cease their management, and only 16.1% of hospitals in Japan currently have PACUs. In today’s efficiency-required atmosphere in Japan, we need to consider a better postoperative management method, including facilities similar to the PACU, to prevent serious adverse events and improve the postoperative outcomes and quality of life. Nevertheless, the way postoperative patients are treated and cared for, and the location in which they receive such attention, will likely need to be modified to fit the Japanese style due to Japan’s unique medical systems and traditions. Here, we describe the past, present and future of the PACU and postanesthesia care in Japan compared with other countries.
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